GABAB receptor explained

gamma-aminobutyric acid (GABA) B receptor, 1
Hgncid:4070
Symbol:GABBR1
Entrezgene:2550
Omim:603540
Refseq:NM_021905
Uniprot:Q9UBS5
Chromosome:6
Arm:p
Band:21.3
gamma-aminobutyric acid (GABA) B receptor, 2
Hgncid:4507
Symbol:GABBR2
Altsymbols:GPR51
Entrezgene:9568
Omim:607340
Refseq:NM_005458
Uniprot:O75899
Chromosome:9
Arm:q
Band:22.1
Locussupplementarydata:-22.3

GABAB receptors (GABABR) are G-protein coupled receptors for gamma-aminobutyric acid (GABA), therefore making them metabotropic receptors, that are linked via G-proteins to potassium channels.[1] The changing potassium concentrations hyperpolarize the cell at the end of an action potential. The reversal potential of the GABAB-mediated IPSP (inhibitory postsynaptic potential) is −100 mV, which is much more hyperpolarized than the GABAA IPSP. GABAB receptors are found in the central nervous system and the autonomic division of the peripheral nervous system.[2]

The receptors were first named in 1981 when their distribution in the CNS was determined, which was determined by Norman Bowery and his team using radioactively labelled baclofen.[3]

Functions

GABABRs stimulate the opening of K+ channels, specifically GIRKs, which brings the neuron closer to the equilibrium potential of K+. This reduces the frequency of action potentials which reduces neurotransmitter release. Thus GABAB receptors are inhibitory receptors.

GABAB receptors also reduces the activity of adenylyl cyclase and Ca2+ channels by using G-proteins with Gi/G0 α subunits.[4]

GABAB receptors are involved in behavioral actions of ethanol,[5] [6] gamma-hydroxybutyric acid (GHB),[7] and possibly in pain.[8] Recent research suggests that these receptors may play an important developmental role.[9]

Structure

GABAB Receptors are similar in structure to and in the same receptor family with metabotropic glutamate receptors.[10] There are two subunits of the receptor, GABAB1 and GABAB2,[11] and these appear to assemble as obligate heterodimers in neuronal membranes by linking up by their intracellular C termini. In the mammalian brain, two predominant, differentially expressed isoforms of the GABAB1 are transcribed from the Gabbr1 gene, GABAB(1a) and GABAB(1b), which are conserved in different species including humans.[12] This might potentially offer more complexity in terms of the function due to different composition of the receptor. Cryo-electron microscopy structures of the full length GABAB receptor in different conformational states from inactive apo to fully active have been obtained. Unlike Class A and B GPCRs, phospholipids bind within the transmembrane bundles and allosteric modulators bind at the interface of GABAB1 and GABAB2 subunits.[13] [14] [15] [16] [17] [18] [19]

Ligands

Agonists

Positive Allosteric Modulators

Antagonists

See also

Notes and References

  1. Chen K, Li HZ, Ye N, Zhang J, Wang JJ . 6433030 . Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro . Brain Research Bulletin . 67 . 4 . 310–8 . October 2005 . 16182939 . 10.1016/j.brainresbull.2005.07.004 .
  2. Hyland NP, Cryan JF . A Gut Feeling about GABA: Focus on GABA(B) Receptors . Frontiers in Pharmacology . 1 . 124 . 2010 . 21833169 . 3153004 . 10.3389/fphar.2010.00124 . free .
  3. Hill DR, Bowery NG . 4335907 . 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA B sites in rat brain . Nature . 290 . 5802 . 149–52 . March 1981 . 6259535 . 10.1038/290149a0 . 1981Natur.290..149H .
  4. Book: Rang and Dale's Pharmacology . Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G . Elsevier, Churchill Livingstone . 2016 . 978-0-7020-5362-7 . 8th . 462 . 903234097.
  5. Dzitoyeva S, Dimitrijevic N, Manev H . Gamma-aminobutyric acid B receptor 1 mediates behavior-impairing actions of alcohol in Drosophila: adult RNA interference and pharmacological evidence . Proceedings of the National Academy of Sciences of the United States of America . 100 . 9 . 5485–90 . April 2003 . 12692303 . 154371 . 10.1073/pnas.0830111100 . 2003PNAS..100.5485D . free .
  6. Ariwodola OJ, Weiner JL . Ethanol potentiation of GABAergic synaptic transmission may be self-limiting: role of presynaptic GABA(B) receptors . The Journal of Neuroscience . 24 . 47 . 10679–86 . November 2004 . 15564584 . 10.1523/JNEUROSCI.1768-04.2004 . 6730127 . free .
  7. Dimitrijevic N, Dzitoyeva S, Satta R, Imbesi M, Yildiz S, Manev H . Drosophila GABA(B) receptors are involved in behavioral effects of gamma-hydroxybutyric acid (GHB) . European Journal of Pharmacology . 519 . 3 . 246–52 . September 2005 . 16129424 . 10.1016/j.ejphar.2005.07.016 .
  8. Manev H, Dimitrijevic N . Drosophila model for in vivo pharmacological analgesia research . European Journal of Pharmacology . 491 . 2–3 . 207–8 . May 2004 . 15140638 . 10.1016/j.ejphar.2004.03.030 .
  9. Dzitoyeva S, Gutnov A, Imbesi M, Dimitrijevic N, Manev H . Developmental role of GABAB(1) receptors in Drosophila . Brain Research. Developmental Brain Research . 158 . 1–2 . 111–4 . August 2005 . 16054235 . 10.1016/j.devbrainres.2005.06.005 .
  10. MRC (Medical Research Council). 2003. Glutamate receptors: Structures and functions. University of Brisotol Centre for Synaptic Plasticity.
  11. Book: Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia AS, McNamara JO, Williams SM . 2001 . 7. Neurotransmitter Receptors and Their Effects . https://www.ncbi.nlm.nih.gov/books/NBK11099/ . Neuroscience . Second . Sinauer Associates, Inc .
  12. Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H, Froestl W, Bettler B . 4345443 . 6 . Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors . Nature . 386 . 6622 . 239–46 . March 1997 . 9069281 . 10.1038/386239a0 . 1997Natur.386..239K .
  13. Shaye H, Stauch B, Gati C, Cherezov V . Molecular mechanisms of metabotropic GABAB receptor function . Science Advances . 7 . 22 . eabg3362 . May 2021 . 34049877 . 10.1126/sciadv.abg3362 . 8163086 . 2021SciA....7.3362S .
  14. Shaye H, Ishchenko A, Lam JH, Han GW, Xue L, Rondard P, Pin JP, Katritch V, Gati C, Cherezov V . 6 . Structural basis of the activation of a metabotropic GABA receptor . Nature . 584 . 7820 . 298–303 . August 2020 . 32555460 . 10.1038/s41586-020-2408-4 . 8020835 . 2020Natur.584..298S .
  15. Papasergi-Scott MM, Robertson MJ, Seven AB, Panova O, Mathiesen JM, Skiniotis G . Nature . Structures of metabotropic GABAB receptor . June 2020 . 584 . 7820 . 310–314 . 10.1038/s41586-020-2469-4 . 32580208 . 7429364 . 2020Natur.584..310P .
  16. Mao C, Shen C, Li C, Shen DD, Xu C, Zhang S, Zhou R, Shen Q, Chen LN, Jiang Z, Liu J, Zhang Y . 219183617 . 6 . B receptor . Cell Research . 564–573 . June 2020 . 30 . 7 . 32494023 . 10.1038/s41422-020-0350-5 . 7343782 .
  17. Park J, Fu Z, Frangaj A, Liu J, Mosyak L, Shen T, Slavkovich VN, Ray KM, Taura J, Cao B, Geng Y, Zuo H, Kou Y, Grassucci R, Chen S, Liu Z, Lin X, Williams JP, Rice WJ, Eng ET, Huang RK, Soni RK, Kloss B, Yu Z, Javitch JA, Hendrickson WA, Slesinger PA, Quick M, Graziano J, Yu H, Fiehn O, Clarke OB, Frank J, Fan QR . 220050861 . 6 . B receptor in an inactive state . Nature . 304–309 . June 2020 . 584 . 7820 . 32581365 . 10.1038/s41586-020-2452-0 . 7725281 .
  18. Kim Y, Jeong E, Jeong JH, Kim Y, Cho Y . Structural Basis for Activation of the Heterodimeric GABAB Receptor . Journal of Molecular Biology . 432 . 22 . 5966–5984 . November 2020 . 33058878 . 10.1016/j.jmb.2020.09.023 . 222841520 .
  19. Shen C, Mao C, Xu C, Jin N, Zhang H, Shen DD, Shen Q, Wang X, Hou T, Chen Z, Rondard P, Pin JP, Zhang Y, Liu J . 6 . Structural basis of GABAB receptor-Gi protein coupling . Nature . 594 . 7864 . 594–598 . June 2021 . 33911284 . 10.1038/s41586-021-03507-1 . 8222003 . 2021Natur.594..594S .
  20. Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, Bettler B, Kaupmann K . 6 . Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501 . Molecular Pharmacology . 60 . 5 . 963–71 . November 2001 . 11641424 . 10.1124/mol.60.5.963 .
  21. Adams CL, Lawrence AJ . CGP7930: a positive allosteric modulator of the GABAB receptor . CNS Drug Reviews . 13 . 3 . 308–16 . 2007 . 17894647 . 6494120 . 10.1111/j.1527-3458.2007.00021.x .
  22. Paterson NE, Vlachou S, Guery S, Kaupmann K, Froestl W, Markou A . Positive modulation of GABA(B) receptors decreased nicotine self-administration and counteracted nicotine-induced enhancement of brain reward function in rats . The Journal of Pharmacology and Experimental Therapeutics . 326 . 1 . 306–14 . July 2008 . 18445779 . 2574924 . 10.1124/jpet.108.139204 .
  23. Urwyler S, Pozza MF, Lingenhoehl K, Mosbacher J, Lampert C, Froestl W, Koller M, Kaupmann K . 26152839 . 6 . N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of gamma-aminobutyric acidB receptor function . The Journal of Pharmacology and Experimental Therapeutics . 307 . 1 . 322–30 . October 2003 . 12954816 . 10.1124/jpet.103.053074 .
  24. Giotti A, Luzzi S, Spagnesi S, Zilletti L . Homotaurine: a GABAB antagonist in guinea-pig ileum . British Journal of Pharmacology . 79 . 4 . 855–62 . August 1983 . 6652358 . 2044932 . 10.1111/j.1476-5381.1983.tb10529.x .
  25. Kimura T, Saunders PA, Kim HS, Rheu HM, Oh KW, Ho IK . Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors . General Pharmacology . 25 . 1 . 193–9 . January 1994 . 8026706 . 10.1016/0306-3623(94)90032-9 .
  26. Froestl W, Gallagher M, Jenkins H, Madrid A, Melcher T, Teichman S, Mondadori CG, Pearlman R . 6 . SGS742: the first GABA(B) receptor antagonist in clinical trials . Biochemical Pharmacology . 68 . 8 . 1479–87 . October 2004 . 15451390 . 10.1016/j.bcp.2004.07.030 .
  27. Bullock R . SGS-742 Novartis . Current Opinion in Investigational Drugs . 6 . 1 . 108–13 . January 2005 . 15675610 .

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